GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression
GRP94 (gp96) and GRP94 N-terminal geldanamycin binding domain elicit tissue nonrestricted tumor suppression
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DOI：
10.1084/jem.20020436
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发表时间：
2002-12-02
影响因子：
15.3
通讯作者：
Nicchitta, CV
中科院分区：
文献类型：
--
作者：
Baker-LePain, JC;Sarzotti, M;Nicchitta, CV
在化学致癌模型中，GRP 94（gp 96）增强肿瘤特异性保护性免疫。这种反应的肿瘤特异性被认为反映了对GRP 94结合肽抗原的免疫反应，其组群唯一地鉴定了GRP 94起源组织。在这项研究中，我们研究了在4 T1乳腺癌模型中GRP 94引起的保护性免疫的明显组织限制。我们报告称，用表达分泌形式GRP 94的照射成纤维细胞接种BALB/c小鼠可显着抑制4 T1肿瘤的生长和转移。此外，用分泌GRP 94 NH 2-末端格尔德霉素结合结构域（NTD）（一个缺乏典型肽结合基序的区域）的辐照细胞接种疫苗，产生了对肿瘤生长和转移进展的类似抑制。条件培养基从培养GRP 94或GRP 94 NTD分泌成纤维细胞引起的主要组织相容性复合物II类和CD 86的上调树突状细胞培养物，与GRP 94和GRP 94 NTD的天然佐剂功能一致。基于这些发现，我们提出GRP 94引起的肿瘤抑制可以独立于GRP 94组织的起源而发生，并表明GRP 4天然佐剂功能在抗肿瘤免疫应答中的主要作用。
In chemical carcinogenesis models, GRP94 (gp96) elicits tumor-specific protective immunity. The tumor specificity of this response is thought to reflect immune responses to GRP94-bound peptide antigens, the cohort of which uniquely identifies the GRP94 tissue of origin. In this study, we examined the apparent tissue restriction of GRP94-elicited protective immunity in a 4T1 mammary carcinoma model. We report that the vaccination of BALB/c mice with irradiated fibroblasts expressing a secretory form of GRP94 markedly suppressed 4T1 tumor growth and metastasis. In addition, vaccination with irradiated cells secreting the GRP94 NH2-terminal geldanamycin-binding domain (NTD), a region lacking canonical peptide-binding motifs, yielded a similar suppression of tumor growth and metastatic progression. Conditioned media from cultures of GRP94 or GRP94 NTD-secreting fibroblasts elicited the up-regulation of major histocompatibility complex class II and CD86 in dendritic cell cultures, consistent with a natural adjuvant function for GRP94 and the GRP94 NTD. Based on these findings, we propose that GRP94-elicited tumor suppression can occur independent of the GRP94 tissue of origin and suggest a primary role for GRP4 natural adjuvant function in antitumor immune responses.